Summary of work: The neuroanatomic and neurophysiologic underpinnings of age- associated cognitive and memory change remain unclear, as there is little information on longitudinal brain changes. We are performing annual magnetic resonance imaging (MRI), positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change. These evaluations will allow us to examine changes in brain structure and function which may be early predictors of cognitive change and impairment, including Alzheimer's Disease (AD). An understanding of these associations and early detection of brain changes will be critical in identifying individuals likely to benefit from new interventions. In addition, we are using neuroimaging tools to investigate modulators of cognitive and brain changes, including genetic risk factors and the effects of sex steroid and other hormones. We are performing studies of the effects of estrogen and androgenic hormones on cognition and the brain in older women and men, respectively. These studies are a follow-up to our observations that estrogen may protect against memory change and AD in post- menopausal women. We published a study of one-year changes in brain structure in a sample of 116 male and female participants aged 56-85 from the Baltimore Longitudinal Study of Aging. Older participants (aged 70-85) had greater ventricular size and smaller gray and white matter volumes on MRI than younger (aged 59-69) participants. Men had greater ventricular volumes and ventricle-to-brain ratios than women suggesting greater brain atrophy in men than women. Longitudinal analysis detected an increase of 1,526 mm3 in ventricular cerebrospinal fluid over one year, but no detectable change over one year in total or regional brain volumes. In a second report, hippocampal volumes were measured for an age, race, and education-matched subsample of individuals positive or negative for the apolipoprotein E (apoE) epsilon 4 allele, a genetic risk factor for AD. Over an average 2.7 year interval, individuals positive for the apoE epsilon 4 allele had a faster rate of hippocampal volume loss. A third report, described differences between women receiving estrogen replacement therapy (ERT) and non-users in longitudinal changes in regional cerebral blood flow (CBF). Compared with nonusers, women taking ERT had better overall memory performance and showed relative increases over 2 years in CBF in some of the brain regions that show pre-clinical abnormalities associated with AD, such as the hippocampus, parahippocampal gyrus, and the middle temporal lobe. In addition these reports, data and support from this project have contributed to a number of methodological developments, including methods for image segmentation, transformation, and analysis. These developments will refine and allow new analyses of our longitudinal neuroimaging data.